Phagocytosis is an essential mechanism for clearance of pathogens, dying cells, and other unwanted debris in order to maintain tissue health in the body. Macrophages execute this process in the peripheral immune system but in the brain microglia act as resident macrophages to accomplish this function. In the peripheral immune system, macrophages secrete Milk Fat Globule Factor-E8 (MFG-E8) that recognizes phosphatidylserine “eat me” signals expressed on the surface of apoptotic cells. MFG-E8 then acts as a tether to attach the apoptotic cell to the macrophage and trigger a signaling cascade that stimulates the phagocyte development, allowing the macrophage to engulf the dying cell. When this process becomes disrupted, inflammation and autoimmunity can result. MFG-E8 resides in the brain as well as in the periphery, and microglia express MFG-E8. However, the function of MFG-E8 in the brain has not been elucidated. We measured MFG-E8 production in the BV-2 microglial cell line and the role of this protein in the recognition and engulfment of apoptotic SY5Y neuroblastoma cells. BV-2 cells produced and released MFG-E8, which apoptotic SY5Y cells and the chemokine fractalkine further stimulated. Furthermore, MFG-E8 increased phagocytosis of apoptotic SY5Y cells, and a dominant negative form of MFG-E8 inhibited phagocytosis by BV-2 cells. Finally, brain MFG-E8 levels were altered in a mouse model of Alzheimer’s disease. Our data suggest that MFG-E8 acts in the brain via microglia to aid in clearance of apoptotic neurons, and we hypothesize that a dysregulation of this process may be involved in neurodegenerative disease.

modulates axo-axonal coupling between neurons critical for learning in the leech. J Neurophysiol 94: [2575][2576][2577][2578][2579][2580][2581][2582][2583][2584][2585][2586][2587][2588][2589] 2005. First published June 29, 2005; doi:10.1152/jn.00322.2005. S cells form a chain of electrically coupled neurons that extends the length of the leech CNS and plays a critical role in sensitization during wholebody shortening. This process requires serotonin, which acts in part by altering the pattern of activity in the S-cell network. Serotonincontaining axons and varicosities were observed in Faivre's nerve where the S-to-S-cell electrical synapses are located. To determine whether serotonin modulates these synapses, S-cell action-potential (AP) propagation was studied in a two-ganglion chain containing one electrical synapse. Suction electrodes were placed on the cut ends of the connectives to stimulate one S cell while recording the other, coupled S cell's APs. A third electrode, placed en passant, recorded the APs near the electrical synapse before they propagated through it. Low concentrations of the gap junction inhibitor octanol increased AP latency across the two-ganglion chain, and this effect was localized to the region of axon containing the electrical synapse. At higher concentrations, APs failed to propagate across the synapse. Serotonin also increased AP latency across the electrical synapse, suggesting that serotonin reduced coupling between S cells. This effect was independent of the direction of propagation and increased with the number of electrical synapses in progressively longer chains. Furthermore, serotonin modulated instantaneous AP frequency when APs were initiated in separate S cells and in a computational model of S-cell activity after mechanosensory input. Thus serotonergic modulation of S-cell electrical synapses may contribute to changes in the pattern of activity in the S-cell network.

The interaction between neurons and glia in the brain is fundamental in keeping the brain healthy. Not only do glia help maintain homeostasis and structural integrity in the brain, they are critical in the removal of harmful material and dying cells. Microglia, which are similar to immune cells in the periphery of the body, are key phagocytic cells in the brain. In the peripheral immune system, macrophages secrete Milk Fat Globule Factor‐E8 (MFG‐E8) that recognizes phosphatidylserine “eat me” signals expressed on the surface of apoptotic cells. MFG‐E8 then acts as a tether to attach the apoptotic cell to the macrophage and trigger a signaling cascade that stimulates the phagocytic capabilities of the macrophage, allowing the macrophage to engulf the dying cell. Meanwhile, an environment of anti‐inflammation is created to protect the surrounding tissue. When this process becomes disrupted, inflammation and autoimmunity can result. MFG‐E8 resides in the brain as well as in the periphery, and recently microglia were shown to express this protein. We propose that MFG‐E8 acts in the brain via microglia as it does in the periphery via macrophages. Our hypothesis is that MFG‐E8 plays a role in microglial phagocytosis of apoptotic neurons, and dysregulation of this process leads to neuroinflammation. Modulation of this mechanism is a potential target for drug discovery in neuroinflammatory disorders such as Alzheimer’s disease. We have confirmed that microglia do produce MFG‐E8 and the major signaling molecules necessary for phagocytic signaling. Our current focus is on demonstrating the involvement of MFG‐E8 in phagocytosis of apoptotic neurons and determining if a similar pathway to the periphery is used in signaling this function.

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